Adhesive preparation

ABSTRACT

An adhesive preparation comprising a stretchable support and an adhesive layer laminated on at least one side of the support, wherein
         the stretchable support comprises a interlock woven fabric subjected to crimping processing,   the adhesive layer contains 10% by mass or more of methyl salicylate with respect to the total mass of the layer,   the whole adhesive preparation has moisture permeability of 1 to 350 g/m 2 ·24 hr measured at a temperature of 40° C. and a relative humidity of 90%, and   the methyl salicylate has a plasma AUC 0-24  ranging from 3.0 to 60.0 ng·hr/mL in terms of a mean±standard deviation, and salicylic acid as a metabolite of the methyl salicylate has a plasma AUC 0-24  ranging from 5000 to 13000 ng·hr/mL in terms of a mean±standard deviation, when the adhesive preparation is applied to a human skin for 8 hours such that an application amount of the adhesive layer applied is 50 to 300 g/m 2  and a contact area is 280 cm 2 .

This is a Continuation application of U.S. patent application Ser. No.12/588,721, filed Oct. 26, 2009, which is a Continuation application ofU.S. patent application Ser. No. 12/227,066, filed Nov. 6, 2008, whichwas filed under 35 U.S.C. 371 as a national stage of PCT/JP2007/065067,filed Aug. 1, 2007, the content of each of which is hereby incorporatedby reference in its entirety.

TECHNICAL FIELD

The present invention relates to an adhesive preparation containingmethyl salicylate.

BACKGROUND ART

Heretofore, anti-inflammatory analgesics for external use, which aresupplemented with a non-steroidal anti-inflammatory agent such as asalicylic acid-based compound (e.g., methyl salicylate), indomethacin,diclofenac, or ketoprofen, and with 1-menthol as a cooling agent, havebeen frequently used, irrespective of patches substantially free frommoisture in an adhesive or poultices containing moisture in an adhesive.However, adhesive preparations containing methyl salicylate have roomfor improvement in terms of analgesic effects, even though they are veryfrequently used.

Non-Patent Documents 1 and 2 have reported that the plasma concentrationof methyl salicylate was measured, when an adhesive preparationsupplemented with methyl salicylate was applied to a human. Of thesedocuments, Non-Patent Document 1 discloses that the plasma concentrationof methyl salicylate hardly rose, when two pieces of adhesivepreparation supplemented with 74.88 mg/piece of methyl salicylate wereapplied to a human, and that a plasma concentration of methyl salicylateof approximately 30 ng/mL was obtained, when eight pieces of suchadhesive preparation were applied to a human.

Non-Patent Document 1: Journal of Clin Pharmacol 2004; 44: 1151-1157

Non-Patent Document 2: Journal of chromatography. B, Biomedical sciencesand applications, Jun. 11, 1999; 729 (1-2): 163-71

DISCLOSURE OF THE INVENTION

As is evident from the description of Non-Patent Document 1, a plasmaconcentration serves as an index for percutaneous absorption, andtherefore, previous adhesive preparations supplemented with methylsalicylate exhibited insufficient percutaneous absorption and as aresult, did not produce sufficient anti-inflammatory analgesic effects.

For obtaining sufficient percutaneous absorption, it is possible, asdescribed in Non-Patent Document 1, that plural adhesive preparationsare simultaneously applied or an adhesive preparation is applied to alarge area. However, such an approach is not practical in considerationof the burdens on the skin. On the other hand, it is also possible thatan adhesive preparation is supplemented with a high concentration ofmethyl salicylate. However, methyl salicylate is a volatile substance.Therefore, even if a usual adhesive preparation is supplemented with ahigh concentration of methyl salicylate, it is difficult to maintain themethyl salicylate at a high concentration in the adhesive preparation,due to volatilization. Moreover, methyl salicylate itself acts as aplasticizer. Therefore, even if an adhesive preparation is supplementedwith a large amount of methyl salicylate, the flexibility of theadhesive preparation, particularly, adhesive layer therein, may bealtered due to subsequent volatilization. Such an adhesive preparationhas the problem that the flexibility or application properties of theadhesive preparation become difficult to control.

The present invention has been completed in consideration of theproblems described above. Specifically, an object of the presentinvention is to provide an adhesive preparation, which, even though itcontains a high concentration of methyl salicylate in an adhesive, canmaintain the methyl salicylate at a high concentration in the adhesive,has favorable application properties, and is capable of being stablypercutaneously absorbed.

The present inventors have conducted diligent studies to attain theobject and have consequently completed the present invention by findingout that an adhesive preparation comprising an adhesive layer containing10% by mass or more of methyl salicylate, which is formed on aparticular stretchable support, wherein the whole adhesive preparationhas particular moisture permeability has excellent applicationproperties and can maintain the sufficient blood concentrations of themethyl salicylate and its metabolite salicylic acid.

Specifically, the present invention provides an adhesive preparationcomprising a stretchable support and an adhesive layer laminated on atleast one side of the support, wherein the stretchable support comprisesa interlock woven fabric subjected to crimping processing, the adhesivelayer contains 10% by mass or more of methyl salicylate with respect tothe total mass of the layer, the whole adhesive preparation has moisturepermeability of 1 to 350 g/m²·24 hr measured at a temperature of 40° C.and a relative humidity of 90%, and the methyl salicylate has a plasmaAUC₀₋₂₄ ranging from 3.0 to 60.0 ng·hr/mL in terms of a mean±standarddeviation, and salicylic acid as a metabolite of the methyl salicylatehas a plasma AUC₀₋₂₄ ranging from 5000 to 13000 ng·hr/mL in terms of amean±standard deviation, when the adhesive preparation is applied to ahuman skin for 8 hours such that an application amount of the adhesivelayer is 50 to 300 g/m² and a contact area is 280 cm². In this context,the plasma concentrations of the drug and the metabolite are measuredaccording to, for example, the guideline of FDA (U.S. Food and DrugAdministration) (Guidance for Industry=Bioanalytical Method Validation).It is preferred that the range from the maximum to minimum values of thenumerical value in a population in which the AUC₀₋₂₄ has been measuredshould be 3 to 200 ng·hr/mL (preferably, 3 to 140 ng·hr/mL, morepreferably 6 to 60 ng·hr/mL) for the plasma AUC₀₋₂₄ of the methylsalicylate and 2500 to 25000 ng·hr/mL (preferably, 2800 to 25000ng·hr/mL, more preferably 2900 to 24000 ng·hr/mL) for the plasma AUC₀₋₂₄of the salicylic acid as a metabolite of the methyl salicylate. Thenumerical range of the “mean±standard deviation” used herein means thatindividual data distribution follows normal distribution, andapproximately 68% thereof falls within the numerical range of the“mean±standard deviation”. More specifically, it means thatapproximately 95% of individual data falls within the numerical range ofthe “mean±double standard deviations”.

The adhesive preparation of the present invention has the particularsupport and moisture permeability within the particular range.Therefore, the adhesive preparation of the present invention has goodskin following properties and can favorably maintain applicationproperties. In addition, the adhesive preparation of the presentinvention, even though it is supplemented with the high concentration ofmethyl salicylate, suppresses the volatilization of the methylsalicylate and is capable of being stably percutaneously absorbed.

According to the adhesive preparation of the present invention, theplasma AUC₀₋₂₄ of methyl salicylate and its metabolite salicylic acid,which is a substance that exhibits anti-inflammatory analgesic effectscan be maintained within particular ranges, and local anti-inflammatoryanalgesic effects can be improved sufficiently. Specifically, accordingto the adhesive preparation of the present invention, the methylsalicylate can have a plasma AUC₀₋₂₄ ranging from 3.0 to 60.0 ng·hr/mLin terms of a mean±standard deviation, and the salicylic acid can have aplasma AUC₀₋₂₄ ranging from 5000 to 13000 ng·hr/mL in terms of amean±standard deviation, when the adhesive preparation is applied to ahuman skin for 8 hours such that an application amount of the adhesivelayer is 50 to 300 g/m² and a contact area is 280 cm².

Moreover, according to the adhesive preparation of the presentinvention, the plasma C_(max) of the methyl salicylate and the salicylicacid can be maintained within particular ranges, and localanti-inflammatory analgesic effects can be improved sufficiently.Specifically, according to the adhesive preparation of the presentinvention, the methyl salicylate can have a plasma C_(max) ranging from2.0 to 40.0 ng/mL in terms of a mean±standard deviation, and thesalicylic acid can have a plasma C_(max) ranging from 700 to 2000 ng/mLin terms of a mean±standard deviation, when the adhesive preparation isapplied to a human skin for 8 hours such that an application amount ofthe adhesive layer is 50 to 300 g/m² and a contact area is 280 cm². Inthis context, the plasma concentrations of the drug and the metaboliteare measured according to, for example, the guideline of FDA (U.S. Foodand Drug Administration) (Guidance for Industry=Bioanalytical MethodValidation). It is preferred that the range from the maximum to minimumvalues of the numerical value in a population in which the C_(max) hasbeen measured should be 2 to 150 ng/mL (preferably, 2 to 130 ng/mL, morepreferably 2 to 125 ng/mL) for the plasma C_(max) of the methylsalicylate and 300 to 4500 ng/mL (preferably, 300 to 3000 ng/mL, morepreferably 450 to 2700 ng/mL) for the plasma C_(max) of the salicylicacid as a metabolite of the methyl salicylate.

It is preferred that the adhesive layer of the present invention shouldcontain 1% by mass or more of 1-menthol with respect to the total massof the adhesive layer. 1-menthol serves as a cooling agent, while1-menthol itself has analgesic effects and also has the effect ofpromoting the percutaneous absorption of the active ingredient.Therefore, 1-menthol is contained in the range described above and canthereby also exhibit local analgesic effects, in addition to salicylicacid. Furthermore, the local percutaneous absorption of the methylsalicylate is promoted. Therefore, local anti-inflammatory analgesiceffects can be further improved.

According to such an adhesive preparation, the plasma AUC₀₋₂₄ andC_(max) of 1-menthol can be maintained within particular ranges, andlocal anti-inflammatory analgesic effects can be further improved.Specifically, according to the adhesive preparation, the 1-menthol canhave a plasma AUC₀₋₂₄ ranging from 30.0 to 130.0 ng·hr/mL in terms of amean±standard deviation and a plasma C_(max) ranging from 5.0 to 20.0ng/mL in terms of a mean±standard deviation, when the adhesivepreparation is applied to a human skin for 8 hours such that anapplication amount of the adhesive layer is 50 to 300 g/m² and a contactarea is 280 cm². In this context, the plasma concentrations of the drugand the metabolite are measured according to, for example, the guidelineof FDA (U.S. Food and Drug Administration) (Guidance forIndustry=Bioanalytical Method Validation). It is preferred that therange from the maximum to minimum values of the numerical value in apopulation in which the plasma AUC₀₋₂₄ and C_(max) of the 1-menthol havebeen measured should be 10 to 300 g·hr/mL (preferably, 10 to 280ng·hr/mL, more preferably 13 to 220 ng·hr/mL) for the plasma AUC₀₋₂₄ and1 to 60 ng/mL (preferably, 2 to 55 ng/mL, more preferably 2 to 30 ng/mL)for the plasma C_(max).

For the adhesive preparation of the present invention, it is preferredthat the interlock woven fabric as the support should have a weight of80 to 150 g/m². If the weight falls within this range, an adhesive basedoes not seep through the stitches of a knitted fabric when the adhesiveis applied to the knitted fabric. Furthermore, anchoring properties withthe adhesive base can be maintained. Thus, application properties as theadhesive preparation can be further improved.

For the adhesive preparation of the present invention, it is preferredthat the adhesive layer should contain a thermoplastic elastomer. Thethermoplastic elastomer is easy to handle and causes a relatively lowirritation to the skin. Therefore, it is preferably used. It ispreferred that the thermoplastic elastomer should be one kind or two ormore kinds selected from the group consisting of astyrene-isoprene-styrene block copolymer, a styrene-butadiene-styreneblock copolymer, a styrene-isoprene rubber, a styrene-butadiene rubber,polyisoprene, polybutadiene, and polyisobutylene.

It is preferred that a content of the thermoplastic elastomer should be25% by mass to 50% by mass with respect to the total mass of theadhesive layer. If the content falls within this range, the cohesion andshape retention of the adhesive layer can be favorably maintained.Accordingly, favorable application properties can be obtained.

Since appropriate tackiness and flexibility can be imparted to theadhesive layer, it is preferred that the adhesive layer should contain arosin-based resin and/or a petroleum-based resin as a tackifier. It ispreferred that a content of the tackifier should be 10% by mass to 30%by mass with respect to the total mass of the adhesive layer. If thecontent falls within this range, the adhesion of the adhesive layer canbe maintained in an appropriate range. Furthermore, the resultingadhesive preparation can be prevented from coming off when applied tothe skin or from causing pain when peeled off.

According to the present invention, the present invention provides anadhesive preparation, which, even though it contains a highconcentration of methyl salicylate in an adhesive, can maintain themethyl salicylate at a high concentration in the adhesive, has good skinfollowing properties, few irritations to the skin, and favorableapplication properties, suppresses the volatilization of the methylsalicylate, and is capable of being stably percutaneously absorbed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing changes in the plasma concentration ofsalicylic acid over time; the maximum plasma concentration (C_(max)) ofsalicylic acid is achieved within twelve (12) hours of administration ofthe adhesive preparation;

FIG. 2 is a diagram showing changes in the plasma concentration ofmethyl salicylate over time; the maximum plasma concentration (C_(max))of methyl salicylate is achieved within six (6) hours of administrationof the adhesive preparation; and

FIG. 3 is a diagram showing changes in the plasma concentration of1-menthol over time; the maximum plasma concentration (C_(max)) of1-menthol is achieved within eight (8) hours of administration of theadhesive preparation.

BEST MODE FOR CARRYING OUT THE INVENTION

An adhesive preparation of the present invention is an adhesivepreparation comprising a stretchable support and an adhesive layerlaminated on substantially the whole surface on at least one side of thesupport.

First, the stretchable support will be described.

The support used in the present invention is an interlock woven fabric(including a knitted fabric) subjected to crimping processing and ispreferably an interlock woven fabric (knitted fabric) subjected tocrimping processing that has two or more tiers of a multifilament yarnof a thermoplastic synthetic resin. This knitted fabric is sufficientlystretchable. Therefore, the adhesive preparation of the presentinvention can firmly follow the skin without coming off or dropping offwhen locally applied, for example, applied to the limbs such as theelbow or the knee. Examples of a preferable material for this knittedfabric include those comprising one kind of or a combination of two ormore kinds of polyester-based, polyethylene-based, andpolypropylene-based materials. Among others, a polyester-based wovenfabric (including a knitted fabric) comprising polyethyleneterephthalate less interacting with a drug is more preferable.

For the knitted fabric as the support, it is preferred that its weight(weight per unit area) should be 80 to 150 g/m². If the weight fallswithin this range, an adhesive base (which refers to an ingredienthaving adhesion, among ingredients constituting the adhesive layer; thesame holds true for the description below) does not seep through thestitches of the knitted fabric when the adhesive described later isapplied to the knitted fabric. Furthermore, anchoring properties withthe adhesive base can be maintained. Thus, the adhesion of the adhesivepreparation can be improved.

Moreover, it is preferred that the support should have a longitudinalmodulus (modulus in the major axis direction) of 2 to 12 N/5 cm and alateral modulus (modulus in the minor axis direction) of 2 to 8 N/5 cmmeasured according to the method of JIS L1018. When the support has amodulus lower than 2 N/5 cm, the adhesive tends to seep into thestitches of the knitted fabric due to the stretched knitted fabric whenapplied thereto, and functions as the adhesive preparation tend to bereduced. On the other hand, when the support has a longitudinal modulushigher than 12 N/5 cm or a lateral modulus higher than 8 N/5 cm, theresulting support is poorly stretchable. Furthermore, such an adhesivepreparation is less likely to follow skin expansion when applied to abend of the body.

Next, the adhesive layer will be described.

The adhesive layer of the present invention comprises an adhesive. Thisadhesive contains a drug methyl salicylate and an adhesive base asessential ingredients. The content of the methyl salicylate in theadhesive layer is 10% by mass or more with respect to the total mass ofthe adhesive layer. The adhesive preparation of the present inventionsupplemented with this concentration of methyl salicylate has thepredetermined support and the predetermined moisture permeability shownlater. Accordingly, the adhesive preparation of the present inventioncan have the plasma concentration of each drug described later and canthereby produce sufficient local analgesic effects. Since the plasmaconcentration of the drug can be maintained more preferably, it ispreferred that the content of the methyl salicylate should be 10 to 15%by mass, more preferably 10 to 12% by mass, with respect to the totalmass of the adhesive layer.

Moreover, for the adhesive preparation of the present invention, it ispreferred that the adhesive layer should further contain 1% by mass ormore of 1-menthol as a drug contained therein. 1-menthol itself hasanalgesic effects and also has the effect of promoting the percutaneousabsorption of the methyl salicylate. Therefore, 1-menthol is containedin this range, and thereby, local anti-inflammatory analgesic effectscan be further improved.

Examples of the adhesive base include thermoplastic elastomer-basedadhesives, acrylic adhesives, rubber-based adhesives (except for theformer two adhesives), polyurethane-based adhesives, silicone-basedadhesives, and adhesives comprising a mixture thereof.

Examples of the thermoplastic elastomer-based adhesives include thosecontaining a thermoplastic elastomer and a tackifier. When thethermoplastic elastomer itself has adhesion, the use of the tackifier isnot essential. The thermoplastic elastomer that can be used in thethermoplastic elastomer-based adhesives can be exemplified bystyrene-isoprene-styrene block copolymers, styrene-butadiene-styreneblock copolymers, polyvinyl acetate, ethylene-vinyl acetate copolymers,styrene-isoprene rubbers, styrene-butadiene rubbers, polyisoprene, andpolybutadiene. Of them, a thermoplastic elastomer-based adhesivecomprising a styrene-isoprene-styrene block copolymer is preferable fromthe viewpoint of cohesiveness, weather resistance, aging resistance, andchemical resistance.

Examples of the styrene-isoprene-styrene block copolymers includeCariflex TR-1107, TR-1111, TR-1112, and TR-1117 (all from ShellChemicals Ltd.), Quintac 3530, Quintac 3421, and Quintac 3570C (all fromZeon Corp.), JSR SIS-5000 and JSR SIS-5002 (all from Japan SyntheticRubber Co., Ltd.), Krayton D-KX401CS and D-1107CU (all from ShellChemicals Ltd.), and Solprene 428 (Phillip Petroleum Company). One kindof or a combination of two or more kinds of them can be used.

Examples of the acrylic adhesives include an adhesive in which at leastone kind of (meth)acrylic monomer such as (meth)acrylic acid,2-ethylhexyl (meth)acrylate, octyl (meth)acrylate, methyl(meth)acrylate, butyl (meth)acrylate, hydroxyethyl (meth)acrylate,glycidyl (meth)acrylate, and methoxyethyl (meth)acrylate is polymerizedor copolymerized at a monomer ratio that exerts adhesion at a usetemperature for the adhesive preparation. A monomer (e.g., vinylacetate) other than the (meth)acrylic monomers can be used as a monomerfor the copolymerization. The acrylic adhesives themselves usually haveadhesion. Therefore, the addition of a tackifier is not essential.However, tackiness, the modulus of elasticity, or the like may becontrolled by the addition of a tackifier.

The acrylic adhesive is preferably a copolymer comprising a high-Tgmonomer (monomer having a glass transition temperature higher than roomtemperature when homopolymerized) and a low-Tg monomer (monomer having aglass transition temperature lower than room temperature whenhomopolymerized) in combination. (Meth)acrylic acid which has polarityand contributes to high adhesiveness is suitable as the high-Tg monomer.(Meth)acrylic acid ester containing an alkyl group having 4 to 12(preferably, 4 to 8) carbon atoms (a hydrogen atom in the alkyl groupmay be substituted by a hydroxy group) is suitable as the low-Tgmonomer.

Examples of the rubber-based adhesives include natural rubber-basedadhesives and polyisobutylene-based adhesives. The natural rubber-basedadhesives comprise a natural rubber and a tackifier. Thepolyisobutylene-based adhesives comprise polyisobutylene having variousmolecular weights and may be supplemented with various additives, ifnecessary. It is particularly preferred that the adhesive comprisingpolyisobutylene should be used as a mixture with astyrene-isoprene-styrene block copolymer.

Examples of the polyurethane-based adhesives include aliphaticpolyurethane adhesives and aromatic polyurethane adhesives. Examples ofthe silicone-based adhesives include an adhesive containing a cruderubber of silicone such as a polydimethylsiloxane polymer,polymethylvinylsiloxane, or polymethylphenylsiloxane and an MQ resin(silicone resin with a three-dimensional structure comprising an “Munit” such as (CH₃)₂SiO_(1/2) and a “Q unit” such as SiO₂).

It is preferred that the content of the adhesive base (the total amountof the adhesive base and the tackifier, if any) should be 35 to 80% bymass, more preferably 40 to 75% by mass, with respect to the total massof the adhesive layer, from the viewpoint of the cohesion and shaperetention of the adhesive layer. When the adhesive base contains atackifier, it is preferred that the content of the ingredient(thermoplastic elastomer or natural rubber) except for the tackifiershould be 25 to 50% by mass, more preferably 30 to 45% by mass, withrespect to the total mass of the adhesive layer. If the content fallsshort of the lower limit described above, elasticity tends to beweakened. Alternatively, if the content exceeds the upper limitdescribed above, shape retention tends to be poor.

The thermoplastic elastomer-based adhesives or the rubber-basedadhesives as the adhesive base usually contain a tackifier for exertingadhesion. A tackifier can be added even to an adhesive base havingadhesion by itself without the addition of the tackifier. Such atackifier is preferably a rosin-based resin and/or a petroleum-basedresin. Examples of the rosin-based resin include natural resin rosin,denatured rosin, rosin ester (e.g., rosin glycerin ester or rosinpentaerythritol ester), and hydrogenated rosin ester (e.g., hydrogenatedrosin glycerin ester or hydrogenated rosin pentaerythritol ester). Amongothers, hydrogenated rosin ester is preferable from the viewpoint ofskin irritation and aging resistance. Hydrogenated rosin glycerin esteris particularly preferable. Specific examples of such a rosin-basedresin include Ester Gum H and Pinecrystal KE-100 and KE-311 (all fromArakawa Chemical Industries, Ltd.) and Foral 85, Foral 105, StaybeliteEster 7, and Staybelite Ester 10 (all from Rika-Hercules, Inc.). Onekind of or a combination of two or more kinds of them can be used.

Moreover, examples of the petroleum-based resin include C5 syntheticpetroleum resins (e.g., copolymers comprising at least two kinds ofisoprene, cyclopentadiene, 1,3-pentadiene, and 1-pentene; copolymerscomprising at least two kinds of 2-pentene and dicyclopentadiene; andresins mainly composed of 1,3-pentadiene), C9 synthetic petroleum resins(e.g., copolymers comprising at least two kinds of indene, styrene,methylindene, and α-methylstyrene), and dicyclopentadiene-basedsynthetic petroleum resins (e.g., copolymers with isoprene and/or1,3-pentadiene mainly composed of dicyclopentadiene). C9 syntheticpetroleum resins are preferable from the viewpoint of weather resistanceand compatibility with the adhesive base.

Moreover, examples of the petroleum resin from the viewpoint of anotherclassification include alicyclic petroleum resins (alicyclic hydrocarbonresins such as alicyclic saturated hydrocarbon resins), alicyclichydrogenated petroleum resins, aliphatic petroleum resins (aliphatichydrocarbon resins), aliphatic hydrogenated petroleum resins, andaromatic petroleum resins. Alicyclic petroleum resins and alicyclichydrogenated petroleum resins are preferable from the viewpoint ofadhesion, compatibility with the adhesive base, and aging resistance.Alicyclic hydrogenated petroleum resins are particularly preferable.Specific examples of such a petroleum-based resin include Arkon P70,Arkon P-90, Arkon P-100, Arkon P-115, and Arkon P-125 (All from ArakawaChemical Industries, Ltd.) and Escoretz 8000 (Esso Chemical Ltd.). Onekind of or a combination of two or more kinds of them can be used.

The adhesive may further contain, in addition to the rosin-based resinand/or the petroleum-based resin, other kinds of tackifiers such asterpene-based resins, phenol-based resins, and xylene-based resins.

The adhesive layer is supplemented with 10% by mass to 30% by mass,preferably 15% by mass to 25% by mass of the tackifier, with respect tothe total mass of the adhesive layer. If the content described above isless than 10% by mass, physical properties of adhesion are easilyreduced, and the resulting adhesion preparation easily comes off whenapplied. If the content exceeds 30% by mass, the resulting adhesionpreparation might cause an irritation to the skin and might cause painwhen peeled off.

The adhesive layer in the adhesive preparation of the present inventionmay contain an absorption promoter, in addition to the drug, theadhesive base, and the tackifier. Such an absorption promoter may be acompound whose effect of promoting absorption into the skin hasheretofore been recognized. Examples thereof include: (1) fatty acid,aliphatic alcohol, fatty acid amide, and fatty acid ether having 6 to 20carbon chains (they may be saturated or unsaturated and may be cyclic,linear, or branched); (2) aromatic organic acids, aromatic alcohol,aromatic organic acid ester, and ether; and (3) lactic acid esters,acetic acid esters, monoterpene-based compounds, sesquiterpene-basedcompounds, Azone, Azone derivatives, glycerin fatty acid esters,propylene glycol fatty acid esters, sorbitan fatty acid esters (Spantype), polysorbates (Tween type), polyethylene glycol fatty acid esters,polyoxyethylene hydrogenated castor oils (HCO type), polyoxyethylenealkyl ethers, sucrose fatty acid esters, and plant oils.

Specifically, caprylic acid, capric acid, caproic acid, lauric acid,myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid,linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleylalcohol, isostearyl alcohol, cetyl alcohol, lauric diethanolamide,myristyl myristate, octyldodecyl myristate, cetyl palmitate, methylsalicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate,cresol, cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate,geraniol, thymol, eugenol, terpineol, 1-menthol, borneol, d-limonene,isoeugenol, isoborneol, nerol, dl-camphor, glycerin monocaprylate,glycerin monocaprate, glycerin monolaurate, glycerin monooleate,sorbitan monolaurate, sucrose monolaurate, polysorbate 20, propyleneglycol monolaurate, polyethylene glycol monolaurate, polyethylene glycolmonostearate, polyoxyethylene oleyl ether, polyoxyethylene lauryl ether,HCO-60, pirotiodecane, and olive oil are preferable. Among them, oleicacid, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearylalcohol, lauric diethanolamide, 1-menthol, glycerin monocaprylate,glycerin monocaprate, glycerin monooleate, sorbitan monolaurate,propylene glycol monolaurate, polyoxyethylene oleyl ether,polyoxyethylene lauryl ether, and pirotiodecane are more preferable.Oleic acid, oleyl alcohol, and 1-menthol are preferably used.

The adhesive layer in the adhesive preparation of the present inventionmay further contain a plasticizer. Examples of such a plasticizerinclude liquid paraffin, petroleum-based oils (e.g., paraffin-basedprocess oil, naphthene-based process oil, and aromatic process oil),squalane, squalene, plant oils (e.g., olive oil, camellia oil, castoroil, tall oil, and peanut oil), silicone oil, dibasic acid ester (e.g.,dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g.,polybutene and liquid isoprene rubbers), and glycol salicylate. Amongthem, liquid paraffin and liquid polybutene are preferably used.

A mixture of two or more kinds of such plasticizers may be used. Thecontent of the plasticizer based on the whole composition constitutingthe adhesive is appropriately determined within the range of 5 to 70% bymass, more preferably 10 to 60% by mass, particularly preferably 10 to50% by mass, with respect to the total mass of the adhesive layer inconsideration of maintaining sufficient permeability and sufficientcohesion as the adhesion preparation.

Moreover, the adhesive layer in the adhesive preparation of the presentinvention may be further supplemented with an antioxidant, a filler, acrosslinking agent, a preservative, a UV absorber, or the like, ifnecessary. Tocopherol and ester derivatives thereof, ascorbic acid,ascorbyl stearate, nordihydroguaiaretic acid, dibutyihydroxytoluene(BHT), butylated hydroxyanisole, and the like are desirable as such anantioxidant. Calcium carbonate, magnesium carbonate, silicate (e.g.,aluminum silicate and magnesium silicate), silicic acid, barium sulfate,calcium sulfate, calcium zincate, zinc oxide, titanium oxide, and thelike are desirable as the filler. Amino resins, phenol resins, epoxyresins, alkyd resins, thermosetting resins (e.g., unsaturatedpolyester), isocyanate compounds, block isocyanate compounds, organiccrosslinking agents, and inorganic crosslinking agents (e.g., metals andmetal compounds) are desirable as the crosslinking agent. Ethylparahydroxybenzoate, propyl parahydroxybenzoate, butylparahydroxybenzoate, and the like are desirable as the preservative.p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylicacid derivatives, coumarin derivatives, amino acid-based compounds,imidazoline derivatives, pyrimidine derivatives, dioxane derivatives,and the like are desirable as the UV absorber.

The adhesive layer is appropriately supplemented with such anantioxidant, a filler, a crosslinking agent, a preservative, or a UVabsorber within the range of 0.01 to 10% by mass, more preferably 0.1 to5% by mass, particularly preferably 0.2 to 2% by mass, with respect tothe total mass of the adhesive preparation.

Moreover, the adhesive preparation of the present invention may furthercomprise, in addition to the support and the adhesive layer, a layer ofa release coating that is peeled off in use. Such an adhesivepreparation is easily produced, stored, and used and is thereforepreferable. Examples of the release coating used in the presentinvention include release paper, cellophane, and synthetic resin films(e.g., polyethylene, polypropylene, polyester, polyvinyl chloride, andpolyvinylidene chloride) subjected to release treatment (e.g., siliconetreatment).

Next, a method for producing the adhesive preparation of the presentinvention will be described.

The adhesive preparation of the present invention can be produced by,but not particularly limited to, a so-called solvent or hot melt method.In the solvent method, the components of the adhesive including the drugare first added at their respective proportions to an organic solventsuch as hexane, toluene, or ethyl acetate, and the mixture is stirred toobtain a uniform dissolved matter. Next, this dissolved matter isexpanded onto a support and then dried with a drier to remove theorganic solvent by volatilization. Then, the dissolved matter is coveredwith a release coating. Or otherwise, the dissolved matter is expandedonto a release coating and then dried with a drier to remove the organicsolvent by volatilization. Then, the dissolved matter may be transferredto a support by compression.

In the hot melt method, the ingredients constituting the adhesive,except for the drug, are first heat-mixed at their respectiveproportions under temperature conditions of 150 to 200° C. in aninactive (e.g., nitrogen) atmosphere. Then, the drug is added thereto,and the mixture is stirred to obtain a uniform melt. This melt isdirectly expanded onto a support and covered with a release coating.Then, the resulting product is cut into a desired shape. Or otherwise,this melt is temporarily expanded onto a release coating and is allowedto further cover a support. Then, the melt is transferred onto thesupport by compression. Then, the resulting product may be cut into adesired shape. The hot melt method is preferably used in terms of goodenergy efficiency and being preferable for workers' health orenvironment.

It is preferred that the thickness (exclusive of the thicknesses of thesupport and the release coating) of the adhesive layer in the adhesivepreparation should be 50 to 300 μm, more preferably 80 to 200 μm. If thethickness is less than 50 μm, the duration of adhesion or adhesivenesstends to be reduced. On the other hand, if the thickness exceeds 300cohesion and shape retention tend to be reduced.

Moreover, it is preferred that the adhesive layer should be formed suchthat the application amount of the adhesive layer (amount of inunction)is 80 to 210 g/m², more preferably 100 to 200 g/m², even more preferably120 to 180 g/m², on the support.

The order described above in which each base ingredient, the drug, andother additive ingredients are added in the production method is merelytaken as an example. The method for producing the adhesive preparationis not intended to be limited to the method with this order of addition.

Next, the moisture permeability of the adhesive preparation of thepresent invention will be described.

It is preferred that the moisture permeability should be 1 to 350g/m²·24 hr, when measured under conditions involving a temperature of40° C. and a relative humidity of 90% according to the method specifiedby JIS Z 208. If the moisture permeability falls within this range, thevolatile methyl salicylate and the 1-menthol that may be added theretoare difficult to volatilize and are stably maintained in the adhesivelayer. Therefore, an effective amount of the drug can be locallypercutaneously absorbed, when the adhesive preparation is applied to theskin. On the other hand, the adhesive preparation itself exhibitsmoisture permeability to some extent. Therefore, even when the adhesivepreparation is applied to the affected part, moisture such as sweatingin this part is moderately evaporated. Therefore, it is considered thatthe adhesive preparation can be applied to the skin for 24 hours orlonger. As a result, the methyl salicylate can be administered morecontinuously. Moreover, the moisture permeability is more preferably 1to 200 g/m²·24 hr, even more preferably 1 to 100 g/m²·24 hr, from theviewpoint of being capable of further exerting the effects describedabove.

The moisture permeability of the adhesive preparation of the presentinvention depends on the thickness of the plaster and the degree ofcompression in the production of the adhesive preparation. Those skilledin the art can appropriately control the moisture permeability to fallwithin the range described above.

Furthermore, the plasma AUC₀₋₂₄ and C_(max) of the drug obtained whenthe adhesive preparation of the present invention is percutaneouslyadministered in an amount of inunction of 50 to 300 g/m² to a 280-cm²area of a human for 8 hours will be described.

In the adhesive preparation of the present invention supplemented with10% or more of methyl salicylate with respect to the total mass of theadhesive layer, the AUC₀₋₂₄ of the methyl salicylate and its metabolitesalicylic acid ranges from 3.0 to 60.0 ng·hr/mL and 5000 to 13000ng·hr/mL, respectively, preferably 13.0 to 48.0 ng·hr/mL and 6300 to11000 ng·hr/mL, respectively, more preferably 20.0 to 40.0 ng·hr/mL and7400 to 10000 ng·hr/mL, respectively, in terms of a mean±standarddeviation under the application conditions described above. Moreover, inthis case, the C_(max) of the methyl salicylate and the salicylic acidranges from 2.0 to 40.0 ng/mL and 700 to 2000 ng/mL, respectively,preferably 9.0 to 34.0 ng/mL and 900 to 1700 ng/mL, respectively, morepreferably 14.0 to 28.0 ng/mL and 1100 to 1500 ng/mL, respectively, interms of a mean±standard deviation. Moreover, when the adhesivepreparation is supplemented with 1% by mass or more of 1-menthol withrespect to the total mass of the adhesive layer, the AUC₀₋₂₄ and C_(max)of the 1-menthol range from 30.0 to 130.0 ng·hr/mL and 5.0 to 20.0ng/mL, respectively, preferably 53.0 to 110.0 ng·hr/mL and 8.0 to 17.0ng/mL, respectively, more preferably 65.0 to 100.0 ng·hr/mL and 10.0 to15.0 ng/mL, respectively, in terms of a mean±standard deviation underthe application conditions described above.

According to the adhesive preparation of the present invention, theparameters within the ranges described above can be obtained. TheAUC₀₋₂₄ and C_(max) depend on the area of the adhesive preparation, thethickness of the plaster, and an individual difference between testsubjects. Those skilled in the art can appropriately control theparameters to fall within the predetermined numerical ranges by use ofthe adhesive preparation of the present invention. Alternatively, whenthe adhesive preparation of the present invention is applied to 70 cm²or other areas for 8 hours, it is obvious that the AUC and C_(max) getsmaller according to the administration area. Moreover, the parametersdescribed above are values obtained by use of the adhesive preparation,and these values are determined by subtracting the value of methylsalicylate, salicylic acid, or 1-menthol before application mixed indaily necessities or the like.

Hereinafter, the present invention will be described more specificallywith reference to Examples. However, the present invention is notintended to be limited to these Examples.

EXAMPLES Examples 1 to 3 Production of Adhesive Preparation

Supports used in Examples 1 to 3 are respectively an interlock wovenfabric of polyethylene terephthalate. Ingredients in each adhesive layerand their proportions are shown in Table 1 below.

TABLE 1 Name of ingredient Example 1 Example 2 Example 3 Methylsalicylate 10 12 15 1-menthol 3.0 3.5 4.5 Styrene-isoprene-styrene block25 30 30 copolymer Polyisobutylene 10 10 10 Liquid paraffin 35 25 20Alicyclic saturated hydrocarbon 17 19.5 20.5 resin (Arkon P-100) Total100 100 100

The components shown in Table 1, except for the drug, were firstheat-mixed at their respective proportions at 150 to 200° C. in aninactive (e.g., nitrogen) atmosphere. Then, the drug was added thereto,and the mixture was stirred to obtain a uniform melt. Next, this meltwas temporarily expanded uniformly onto a release coating and wasallowed to further cover a support. Then, the melt was transferred ontothe support by compression to form an adhesive layer (amount ofinunction: 120 g/m²) on the support. Then, the resulting product was cutinto a 280 cm² square to produce an adhesive preparation.

Example 4 Measurement of Moisture Permeability

The moisture permeability of the adhesive preparations of Examples 1 and3 was measured at a temperature of 40° C. and a relative humidity of 90%according to the cup method (JIS Z0208).

Test pieces (n=3) used were obtained by stamping the adhesivepreparations produced according to Examples 1 and 3 into a round shapeof approximately 70 mm in diameter. A moisture absorbent used wasanhydrous calcium chloride (which has a particle size that passesthrough a 2380 μm standard sieve but remains on a 590 μm standardsieve). A cup used was Y.S.S Tester No. 3525 (Yasuda Seiki Seisakusho,Ltd.).

A glass dish containing the moisture absorbent was placed in the cup,and this cup was placed on a cup table kept in a horizontal position.The test piece was placed over the cup at a position concentric with thecup, with the support in the adhesive preparation turned up. A guide wasput on the cup such that the guide fitted in a groove of the cup table.A ring was forced thereinto along with the guide until the test piececame into tight contact with the upper edge of the cup. A weight wasplaced thereon. Then, the guide was removed by vertically pulling it upwith care not to move the ring. Next, the cup was horizontally rotated,while a molten sealing wax was poured into the groove on the peripheryof the cup to seal the edge of the test piece. After the sealing wax wassolidified, the weight and the cup table were removed to obtain samples(n=3).

The initial mass of the cup was measured. Then, the sample was left in athermo-hygrostat kept under test conditions involving a temperature of40° C. and a relative humidity of 90% and taken out the sample after 24hours. The sample was stored in a desiccator for 30 minutes and weighed.This procedure was repeated twice to measure the mass of the cup. Avalue obtained by subtracting the initial mass from this mass wasdefined as an amount of increase in mass. The amount of increase in massconverted to a value per m² was used as moisture permeability (g/m²·24h).

As a result, the moisture permeability of the adhesive preparations ofExamples 1 and 3 was 5 to 120 g/m²·24 h and 5 to 185 g/m²·24 h,respectively.

Example 5 Measurement of Plasma Concentration

The 280-cm² adhesive preparation (methyl salicylate: 336 mg; 1-menthol:100 mg) of Example 1 was applied to seven healthy adults for 8 hours.Blood was collected over time. The blood collection was performed oneach of 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours from thestart of the application, and the amount of blood collected each timewas 7 mL. Methyl salicylate and 1-menthol are contained in large amountsin daily necessities. Therefore, the use of such daily necessities wasavoided before and during the application.

The plasma concentrations of the methyl salicylate, its metabolitesalicylic acid, and the 1-menthol were separately measured. Themeasurement was performed by liquid chromatography-mass spectrometry forthe salicylic acid and by gas chromatography-mass spectrometry for themethyl salicylate and the 1-menthol. Each of the measurement methods wasvalidated beforehand to confirm measurement reliability. Values obtainedby subtracting an endogenous concentration (measurement value on 0 hour)before the application from an actual measurement value were used asplasma concentrations during the application. The C_(max) and AUC₀₋₂₄were calculated according to the standard methods.

Changes in the plasma concentrations of the salicylic acid, the methylsalicylate, and the 1-menthol over time are shown in FIGS. 1 to 3. Theirrespective pharmacokinetic parameters are shown in Table 2. A mean wasan average value from the seven individuals to be tested. Thismeasurement of the plasma concentrations was performed according to theguideline of FDA (U.S. Food and Drug Administration) (Guidance forIndustry=Bioanalytical Method Validation).

TABLE 2 AUC₀₋₂₄ Cmax (ng · hr/mL) (ng/mL) Salicylic acid Mean ± S.D.6255 ± 2706 1078 ± 409 Minimum value 3948 705 Maximum value 11769 1771Methyl salicylate Mean ± S.D. 24.9 ± 14.3  14.6 ± 10.9 Minimum value 8.13.5 Maximum value 50.0 33.0 1-menthol Mean ± S.D. 53.6 ± 33.4 10.7 ± 6.4Minimum value 15.4 4.5 Maximum value 109 22.5

When each of the plasma parameters thus obtained is compared with avalue obtained by subtracting a value on 0 hour from the plasmaconcentration of methyl salicylate or menthol measured in Non-PatentDocument 1, the C_(max) and AUC₀₋₂₄ of the methyl salicylate and thementhol in the applied 280 cm² of adhesive preparation (methylsalicylate: 336 mg; 1-menthol: 100 mg) of the present invention wereclose to values of eight adhesive preparations (methyl salicylate: 74.88mg×8=599 mg; menthol: 37.44×8=299.5 mg) applied in Non-PatentDocument 1. This demonstrated that according to the adhesive preparationof the present invention, the sufficient plasma concentration of eachactive ingredient is obtained. It is considered that the localpercutaneous absorption of the active ingredient is also sufficient byvirtue of the adhesive preparation of the present invention. Thus, it isconsidered that the adhesive preparation of the present inventionimproves local anti-inflammatory analgesic effects.

Example 6 Measurement of Plasma Concentration

A similar experiment to that in Example 5 was conducted on 101 healthyadults. As a result, the methyl salicylate had an AUC₀₋₂₄ of 139.0ng·hr/mL as a maximum value, 3.7 ng·hr/mL as a minimum value, and 30.1ng·hr/mL as a mean and a C_(max) of 109.4 ng/mL as a maximum value, 2.5ng/mL as a minimum value, and 21.1 ng/mL as a mean (however, the AUC₀₋₂₄of the methyl salicylate was a measurement result from 48 out of the 101individuals). Moreover, the salicylic acid had an AUC₀₋₂₄ of 24731ng·hr/mL as a maximum value, 3464 ng·hr/mL as a minimum value, and 8848ng·hr/mL as a mean and a C_(max) of 4100 ng/mL as a maximum value, 531ng/mL as a minimum value, and 1291 ng/mL as a mean. Furthermore, the1-menthol had an AUC₀₋₂₄ of 273.0 ng·hr/mL as a maximum value, 11.1ng·hr/mL as a minimum value, and 80.6 ng·hr/mL as a mean and a C_(max)of 51.0 ng/mL as a maximum value, 2.6 ng/mL as a minimum value, and 12.4ng/mL as a mean. Their respective pharmacokinetic parameters are shownin Table 3. This measurement of the plasma concentrations was performedaccording to the guideline of FDA (U.S. Food and Drug Administration)(Guidance for Industry=Bioanalytical Method Validation).

TABLE 3 AUC₀₋₂₄ Cmax (ng * hr/mL) (ng/mL) Salicylic acid Mean ± S.D.8848 ± 3684 1291 ± 543 Minimum value 3464 531 Maximum value 24731 4100Methyl salicylate Mean ± S.D. 30.1 ± 25.6  21.1 ± 18.2 Minimum value 3.72.5 Maximum value 139.0 109.4 1-menthol Mean ± S.D. 80.6 ± 41.2 12.4 ±6.7 Minimum value 11.1 2.6 Maximum value 273.0 51.0

The adhesive preparation of Example 1 could firmly follow the skinwithout coming off or dropping off and caused no irritation to the skinwhen applied thereto for 8 hours.

The invention claimed is:
 1. An adhesive preparation comprising: astretchable support and an adhesive layer, wherein the adhesive layer islaminated on at least one side of the support and comprises athermoplastic elastomer, and 10% by mass or more of methyl salicylatewith respect to the total mass of the layer, wherein the whole adhesivepreparation has moisture permeability of 1 to 350 g/m²·24 hr measured ata temperature of 40° C. and a relative humidity of 90%, and wherein aplasma C_(max) of salicylic acid is achieved within 12 hours ofadministration of the adhesive preparation.
 2. The adhesive preparationaccording to claim 1, wherein the adhesive layer comprises a tackifier.3. The adhesive preparation according to claim 2, wherein the tackifiercomprises one or more selected from the group consisting of arosin-based resin and a petroleum-based resin.
 4. The adhesivepreparation according to claim 2, wherein the tackifier is present inthe adhesive preparation from 10% by mass to 30% by mass with respect tothe total mass of the adhesive layer.
 5. The adhesive preparationaccording to claim 1, wherein the stretchable support comprises alongitudinal modulus of 2 to 12 N/5 cm and a lateral modulus of 2 to 8N/5 cm.
 6. The adhesive preparation according to claim 1, wherein thestretchable support comprises a weight per unit area of 80 to 150 g/m².7. The adhesive preparation according to claim 1, wherein thestretchable support comprises an interlock woven fabric.
 8. The adhesivepreparation according to claim 1, wherein adhesive layer contains 1% bymass or more of I-menthol with respect to the total mass of the layer.9. The adhesive preparation according to claim 1, wherein thethermoplastic elastomer is one or more selected from the groupconsisting of a styrene-isoprene-styrene block copolymer, astyrene-butadiene-styrene block copolymer, a styrene-isoprene rubber, astyrene-butadiene rubber, polyisoprene, polybutadiene, andpolyisobutylene.
 10. The adhesive preparation according to claim 1,wherein the thermoplastic elastomer is present in the adhesivepreparation from 25% by mass to 50% by mass with respect to the totalmass of the adhesive layer.